Acute effects of GIP and GLP‐1 receptor antagonism in totally pancreatectomized individuals: A randomized double‐blind, placebo‐controlled crossover study

Aims The incretin hormones glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide 1 (GLP‐1) influence metabolism through strong effects on pancreatic hormone secretion but also in a pancreas‐independent manner. Here, we investigated the isolated extrapancreatic effects of endogenous GIP and GLP‐1 by applying hormone receptor antagonists in totally pancreatectomized individuals. Methods Twelve totally pancreatectomized individuals each underwent four 270‐min liquid mixed meal tests (480 kcal) in a randomized study design with infusions of the GIP receptor antagonist GIP(3‐30)NH 2 (800 pmol/kg/min), the GLP‐1 receptor antagonist exendin(9‐39)NH 2 (450 pmol/kg/min), GIP(3‐30)NH 2 + exendin(9‐39)NH 2 , and saline (placebo), respectively. Blood samples, appetite‐related measures, heart rate, blood pressure, and ad libitum food intake data were collected. Participants continued their basal insulin but omitted bolus insulin in the morning of the experiment. Results Infusions of GIP(3‐30)NH 2 and GIP(3‐30)NH 2 + exendin(9‐39)NH 2 attenuated meal‐induced inhibition of bone resorption (carboxy‐terminal collagen crosslinks) (nadir [mean ± SD] to 84 ± 9% and to 85 ± 8% of baseline, compared to placebo (64 ± 15%) ( p s <0.05)). During exendin(9‐39)NH 2 and exendin(9‐39)NH 2 + GIP(3‐30)NH 2 co‐infusion, GLP‐1 plasma responses increased ( p s <0.05). Infusion of GIP(3‐30)NH 2 or exendin(9‐39)NH 2 did not affect other measurements. Conclusion Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP‐1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets.